Title: Therapeutic Targeting of MMP-12 for the Treatment of Chronic Obstructive Pulmonary Disease.
Authors: Baggio, Carlo; Velazquez, Jalene V; Fragai, Marco; Nordgren, Tara M; Pellecchia, Maurizio
Published In J Med Chem, (2020 11 12)
Abstract: Chronic obstructive pulmonary disease (COPD) is a lung disorder characterized by progressive airflow obstruction associated with inflammation and emphysema, and it is currently one of the leading causes of death worldwide. Recent studies with genetically engineered mice reported that during pulmonary inflammation, basophil-derived interleukin-4 can act on lung-infiltrating monocytes causing aberrant expression of the matrix metalloproteinase-12 (MMP-12). MMP-12 activity in turn causes the destruction of alveolar walls leading to emphysema, making it potentially a valid target for pharmacological intervention. Using nuclear magnetic resonance (NMR)- and structure-based optimizations, the current study reports on the optimized novel, potent, and selective MMP-12 inhibitors with single-digit nanomolar affinity in vitro and in vivo efficacy. Using a murine model of elastase-induced emphysema we demonstrated that the most potent agents exhibited a significant decrease in emphysema-like pathology compared to vehicle-treated mice, thus suggesting that the reported agents may potentially be translated into novel therapeutics for the treatment of COPD.
PubMed ID: 33107733
MeSH Terms: Animals; Binding Sites; Crystallography, X-Ray; Disease Models, Animal; Emphysema/drug therapy; Emphysema/etiology; Half-Life; Humans; Isoenzymes/antagonists & inhibitors; Isoenzymes/metabolism; Matrix Metalloproteinase 12/chemistry; Matrix Metalloproteinase 12/metabolism*; Matrix Metalloproteinase Inhibitors/chemistry*; Matrix Metalloproteinase Inhibitors/pharmacokinetics; Matrix Metalloproteinase Inhibitors/therapeutic use; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular Dynamics Simulation; Nuclear Magnetic Resonance, Biomolecular; Pancreatic Elastase/metabolism; Peptides/genetics; Peptides/metabolism; Peptides/therapeutic use; Pulmonary Disease, Chronic Obstructive/drug therapy; Pulmonary Disease, Chronic Obstructive/pathology; Structure-Activity Relationship